This invention relates to the use of a lymphokine, alone or in combination with other lymphokines, in the prophylactic or therapeutic treatment of infectious diseases.
It has long been known that microbial infection can be inhibited by a variety of immunomodulating agents. These agents may be classified as: (1) crude immunostimulant of microbial nature (examples are mycobacterium boris strain BCG and the killed vaccine of corynebacterium parvum); and (2) chemically defined immunoadjuvants of bacterial origin (examples are lipopolysaccharides). More recently, various synthetic immunomodulating drugs have been shown to possess antiviral effects. The most promising of these, Inosiplex, has been tested in man and claimed to be effective against a variety of virus infections (Hepatitis A, recurrent Herpes Simplex, Herpes Zoster, influenza-caused common cold). The response, however, has not always been predictable and appears to vary with individual patients.
Lymphokines, such as interleukin-2, interferon-alpha, interferon-gamma, colony stimulating factor, and tumor necrosis factor, are proteins secreted by T cells upon activation by antigens or lectins. Interleukin-2, a lymphokine which is produced by normal peripheral blood lymphocytes and induces proliferation of antigen or mitogen stimulated T cells after exposure to plant lectins, antigens, or other stimuli, was first described by Morgan, D. A., et at., Science (1976) 193: 1007-1008. Then called T cell growth factor because of its ability to induce proliferation of stimulated T lymphocytes, it is now recognized that in addition to its growth factor properties it modulates a variety of functions of immune system cells in vitro and in vivo and has been renamed interleukin-2 (IL-2). IL-2 is one of several lymphocyte-produced, messenger-regulatory molecules which mediate immunocyte interactions and functions.
IL-2 was initially made by cultivating human peripheral blood lymphocytes (PBL) or other IL-2-producing cell lines. See, for example, U.S. Pat. No. 4,401,756. Recombinant DNA technology has provided an alternative to PBLs and cell lines for producing IL-2. Taniguchi, T. et al., Nature (1983), 302:305-310 and Devos, R., Nucleic Acids Research (1983), 11:4307-4323 have reported cloning the human IL-2 gene and expressing it in microorganisms.
U.S. Pat. No. 4,518,584 describes and claims muteins of IL-2 in which the cysteine normally occurring at position 125 of the wild-type or native molecule has been replaced with a neutral amino acid, such as serine or alanine. Copending U.S. application Ser. No. 810,656 filed Dec. 17, 1985 discloses and claims an oxidation-resistant mutein such as IL-2 which is biologically active wherein each methionine residue of the protein from which the mutein is derived which methionine is susceptible to chloramine T or peroxide oxidation is replaced with a conservative amino acid such as alanine. These IL-2 muteins are disclosed as useful in combating bacterial, viral, fungal, parasitic and protozoan infections. U.S. Pat. Nos. 4,530,787 and 4,569,790 disclose and claim methods for purifying recombinant native IL-2 and muteins thereof, as well as the purified form of IL-2.
U.S. Pat. No. 4,604,377 issued Aug. 5, 1986 (PCT W085/04328) discloses an IL-2 composition suitable for reconstituting in a pharmaceutically acceptable aqueous vehicle composed of oxidized microbially produced recombinant IL-2. The IL-2 is noted as useful in enhancing cell-mediated immune responses in the therapy of viral, parasitic, bacterial, malignant, fungal, protozoal, or mycobacterial or other infectious diseases. In addition, the IL-2 is disclosed as useful for inducing enhanced immunologic response of cells ex vivo in treating infectious diseases, for prophylaxis against infectious diseases and for treating infectious diseases in combination with other lymphokines. The effect of IL-2 on host resistance mechanisms before the onset of specific immune responses has not been studied to applicants' knowledge.
IL-2 is also disclosed as useful as an anti-infective in WO 85/05124 published Nov. 21, 1985 (Sandoz), WO 85/03948 published Sept. 12, 1985 (Celltech), EP 147,819 published July 10, 1985 (Hoffmann-LaRoche), EP 118,617 published Sept. 19, 1984 (Ajinomoto), EP 118,977 published Sept. 19, 1984 (Biogen), Siegel et al., Infection, 13,:219-223 (1985), Siegel et al., Infection, 12:298-302 (1984, Lane et al., Cancer Res., 45:4674-4676 (1985), Rouse et al., J. Immunol., 134:926-930 (1985, EP 132,754 published Feb. 13, 1985 (Rockefeller University), EP 94,317 published Nov. 16, 1983 (Shionogi), U.S. Pat. Nos. 4,407,945 and 4,473,642 (Immunex), EP 142,268 published May 22, 1985 (Ajinomoto), and EP 89,062 published Sept. 21, 1983 (Ajinomoto). None of these references appear to disclose specific in vivo activity of the IL-2.
Tumor necrosis factor (TNF) was first described by Carswell et al., PNAS (USA) (1975) 72:3666-3670 as an endotoxin-induced serum factor which causes necrosis of chemically transformed tumor cells when growing in mice. Human TNF is known to be cytotoxic to neoplastic cells, and has been produced in recombinant form. See Pennica et al., Nature (London) (1984) 312:724-729 and Shirai et al., Nature (London) (1985) 313:803-806, Wang et al., Science (1985), 228:149-154.
The cloning of rabbit TNF is disclosed in EP No. 146,026, published June 26, 1985 (Dainippon Pharmaceutical Co., Ltd.) and EP No. 148,311, published July 17, 1985 (Asahi Kasei Kogyo Kabushiki). The cloning of human TNF having 151 and 155 amino acids (2 and 6 less than the native form) is disclosed in EP No. 155,549, published Sept. 25, 1985 (Dainippon Pharmaceutical Co., Ltd.), and human TNF having 155 amino acids is disclosed in EP No. 158,286, published Oct. 16, 1985 (Asahi Kasei Kogyo Kabushiki Kaisha) and corresponding GB No. 2,158,829A, published Nov. 20, 1985. The cloning of mature TNF (157 amino acids) and various modified forms (muteins) thereof is disclosed in EP No. 168,214, published Jan. 15, 1986 (Genentech) and PCT No. US85/01921, filed Oct. 3, 1985, published Apr. 1986 (Cetus Corporation). The latter, PCT No. 85/01921 corresponds to U.S Pat. No. 4,677,063 issued June 30, 1987, the disclosure of which is incorporated herein by reference.
Interferons (IFN) constitute a group of naturally occurring proteins which are known to exhibit anti-viral, anti-tumor and immunoregulatory behavior. Two types of IFN have been identified based on differences in their observed biological properties and molecular structures: Type I and Type II. Beta-interferon (IFN-.beta.) is a Type I IFN which can be induced in fibroblasts by viral challenge and contains about 165 amino acids. IFN-.alpha. is also a Type I IFN inducible in leukocytes, and IFN-.gamma. is a Type II IFN which is induced in lymphocytes in response to specific mitogenic stimuli and contains 146 amino acids.
It is known that Type I and Type II interferons (IFN) may be combined to produce a synergistic biological effect. See, for example, Fleishmann, Cancer Res. (1982) 42:869-875 (mouse IFNs) and European Patent Publication No. 107,498 published May 2, 1984 (human IFN-.gamma. and IFN-.alpha. or .beta.). U.S. Pat. No. 4,518,584 to Mark et al. (Cetus Corporation) discloses the combination of IL-2 muteins with gamma-interferon, B cell growth factor, and IL-1. In addition, it has been disclosed that IL-2 may be used with IFN-.gamma. to treat tumor-bearing hosts with synergistic results (European Patent Publication No. 149,551 published July 24, 1985 (Genentech) and German Patent Publication No. 3411184 published Oct. 31, 1985 (Deut Roten Kreuzes)) or with augmentation of natural killer activity (Svedersky et al., J. Immunol. (1984) 133:714-718). Also, Dr. Talmadge of the Preclinical Screening Lab, BRMP has reported in 1986 the augmented effect of using TNF and IFN-.gamma. to treat metastatic disease in mice. EP No. 131,789, published Jan. 23, 1985 (Sloan-Kettering Institute for Cancer Research) and EP No. 168,214, published Jan. 15, 1986 (Genentech) disclose the synergistic effect of TNF and IFN-.gamma. to treat various tumors in mice.
The effect of various lymphokines, alone or in combination, on infectious diseases in vivo has not been extensively studied to date.